This cross-species translational research program will use laboratory-based inhibitory biomarkers (IBs) to understand the genetic and neurobiological basis for the group of schizophrenias. The overarching goal of this project is to identify genetic variation associated with deficits in specific IBs in schizophrenia patients, and in parallel, to use animal model studies to clarify the neurobiological mechanisms linking these genes and IB deficits, i.e. the gene-to-phene gap. In schizophrenia patients and normal comparison subjects, measures will assess 3 extensively studied primary IBs with known schizophrenia-linked deficits - prepulse inhibition of startle (PPI), startle habituation (HAB), and event related potentials (ERPs). IBs, their interrelationships, and associations with demographic, clinical, neurocognitive and functional outcomes will be examined. In mice and rats, PPI, HAB, and ERPs will be measured. In Aim 1, haplotype analyses will refine our preliminary IB-gene results. The genetic architecture of each IB in schizophrenia patients will be examined, focusing on 3 genes - NRG1; ERBB4; and COMT - together with other secondary genes of interest, based on preliminary association findings and/or the extant literature. Gene path analyses will more clearly define gene-gene interactions underlying biomarker-defined subgroups. Aim 2 will test 400 new schizophrenia patients and 400 new normal comparison subjects. These 800 new subjects will provide the power necessary to conduct the proposed behavioral and genetic analyses. Fine mapping will be performed to clarify the genetic substrates of biomarkers using the inclusive sample as well biomarker-defined subgroups based on the extreme deciles and quartiles of the distribution of IB measures. In Aim 3, pharmacological and molecular studies in rodents will explicate novel genetic mechanisms underlying IB deficits by: 1) assessing the impact of neuregulin-1 fragments on the IB deficits induced by dopamine agonists and NMDA antagonists in rats and mice; 2) assessing IB deficits in interneuron-specific ErbB4 knock out mice; and 3) characterizing knock in mice having Val/Val or Met/Met variants of the human COMT gene, complemented by regionally specific viral delivery of the COMT gene. Aim 4 will characterize changes in brain regional gene expression in rat models with construct validity for IB deficits in schizophrenia patients: neonatal ventral hippocampal lesions (NVHLs) and isolation rearing. RT-PCR studies in inbred rats will focus on genes found in preliminary cross-species studies to be associated with IB deficits (e.g. NRG1, ERBB4, COMT, GRID2, REELIN, and GRIN2B). Functional (neurochemical) consequences of differences in regional gene expression will also be confirmed in NVHL and isolation-reared rats. In aggregate, these 4 Aims will leverage powerful translational strategies to identify genes associated with IB deficits in schizophrenia patients, and to explicate the neurobiological mechanisms that mediate these associations.